Glucokinase (sometimes to be abbreviated to GK in the present specification) (EC2.7.1.1) is one of the four kinds of hexokinases found in mammals, and is also called hexokinase IV. GK is an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate, which is the first step of glycolysis. GK is mainly present in the pancreatic β cell and the liver, and acts in the pancreatic β cell as a sensor of extracellular glucose concentration that regulates the glucose-stimulated insulin secretion. In the liver, the enzyme reaction of GK is a rate determining factor which regulates glycogen synthesis and glycolysis. The three hexokinases (I, II, III) other than GK reach the maximum enzyme activity at a glucose concentration of 1 mM or below. In contrast, GK shows low affinity for glucose and has a Km value of 8-15 mM which is close to a physiological blood glucose level. Accordingly, GK-mediated promotion of intracellular glucose metabolism occurs in conjunction with blood glucose changes from normal blood glucose (5 mM) to postprandial hyperglycemia (10-15 mM).
The hypothesis proposed by Matschinsky et al. in 1984 that GK acts as a glucose sensor in the pancreatic β cell and hepatocytes has been demonstrated by the analysis of glucokinase transgenic mouse in recent years (see The Journal of Biological Chemistry (J. Biol. Chem.), 1995, vol. 270, page 30253-30256; The Journal of Biological Chemistry (J. Biol. Chem.), 1997, vol. 272, page 22564-22569; The Journal of Biological Chemistry (J. Biol. Chem.), 1997, vol. 272, page 22570-22575; NIHONRINSHO, 2002, vol. 60, page 523-534; and Cell, 1995, vol. 83, page 69-78). That is, GK heterozygous deficient mouse showed a hyperglycemic condition, and further, a disordered glucose-stimulated insulin secretion response. GK homozygous deficient mouse dies shortly after birth with manifestations of marked hyperglycemia and urinary sugar. On the other hand, GK overexpressed mouse (hetero type) showed decreased blood glucose level, increased blood glucose clearance rate, increased liver glycogen content and the like. From these findings, it has been clarified that GK plays an important role in the systemic glucose homeostasis. In other words, decreased GK activity causes insulin secretion failure and lower liver glucose metabolism, which develops impaired glucose tolerance and diabetes. Conversely, GK activation or increased GK activity due to overexpression causes promoted insulin secretion and promoted liver glucose metabolism, which in turn increases the systemic use of glucose to improve glucose tolerance.
In addition, it has been clarified from the analysis of a report on GK gene abnormality mainly in the family of MODY2 (Maturity Onset Diabetes of the Young) that GK also acts as a glucose sensor in human, and plays a key role in glucose homeostasis (see Nature, 1992, vol. 356, page 721-722). In GK gene abnormality, due to the decreased affinity of GK for glucose (increased Km value) and the decreased Vmax, the blood glucose threshold value of insulin secretion increases and the insulin secretory capacity decreases. In the liver, decreased glucose uptake, promoted gluconeogenesis, decreased glycogen synthesis and liver insulin resistance are observed due to the decreased GK activity. On the other hand, a family with a mutation increasing the GK activity has also been found. In such a family, fasting hypoglycemia associated with increased plasma insulin concentration is observed (see New England Journal Medicine, 1998, vol. 338, page 226-230).
As mentioned above, GK acts as a glucose sensor in mammals including human, and plays an important role in blood glucose regulation. On the other hand, the control of blood glucose utilizing the glucose sensor system of GK is considered to open a new way to treat diabetes in many type 2 diabetes patients. Particularly, since a GK activating substance is expected to show insulin secretagogue action in the pancreatic β cell and glucose uptake promotion and glucose release suppressive action in the liver, it will be useful as a prophylactic or therapeutic drug for type 2 diabetes.
In recent years, it has been clarified that pancreatic β cell type glucokinase expresses locally in the feeding center (Ventromedial Hypothalamus: VMH) of rat brain. A subset of nerve cell present in VMH is called glucose responsive neuron, and plays an important role in the body weight control. From electrophysiological experiments, the neuron is activated in response to physiological changes in the glucose concentration (5-20 mM). However, since the glucose concentration sensor system of VHM is assumed to have a mechanism mediated by glucokinase as in the case of insulin secretion in the pancreatic β cell, different from the pancreatic β cell and the liver, a medicament capable of activating glucokinase of VHM has a possibility of providing not only a blood glucose corrective effect but also improvement of obesity.
As mentioned above, a medicament capable of activating GK is useful as a prophylactic or therapeutic drug for diabetes, diabetic complications, obesity and the like.
The following compounds have been reported.    (1) It has been reported that a compound represented by the formula:
wherein    R1, R2, R3, R4, R6 and R7 are each independently a hydrogen atom, a halogen atom, nitro, —CN, —OH, —COOH, —CF3, —NR10R11 (R10 and R11 are each independently a hydrogen atom, a C1-6 alkyl group, —CO—1-6 alkyl, carboxy-C1-6 alkyl, —C—C1-6 alkyl-COOH, —SO2CH3, an aryl group etc.), a C1-6 alkyl group, a C3-8 cycloalkyl group, a heteroaryl group and the like;    R5 is a C1-6 alkyl group and the like; and    A is optionally substituted thiazolyl and the like is a glucokinase activator, and useful for the treatment of diabetes and the like (patent document 1).    (2) It has been reported that a compound represented by the formula:
wherein    ring A is an optionally substituted 6-membered ring,    W is O, S(O)m (m is 0, 1 or 2), CR5R6 (R5 and R6 are each independently a hydrogen atom or a C1-6 alkyl group) or NR7 (R7 is a hydrogen atom or R3′—Y′— (R3′ is an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted mercapto group, an optionally substituted amino group or an optionally substituted heterocyclic group, Y′ is a bond, CO, S(O)q (q is 0, 1 or 2) or CR8′R9′ (R8′ and R9′ are each independently a hydrogen atom or a C1-6 alkyl group),    Y is a bond, CO, S(O)p (p is 0, 1 or 2) or CR8R9 (R8 and R9 are each independently a hydrogen atom or a C1-6 alkyl group),    R3 is an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted mercapto group, an optionally substituted amino group or an optionally substituted heterocyclic group,    Z is a bond, CO, O, S(O)n (n is 0, 1 or 2) or NR10 (R10 is a hydrogen atom or a C1-6 alkyl group),    R1 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted mercapto group,    R2 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted mercapto group, an optionally substituted amino group or an optionally substituted heterocyclic group, and R1 and R2 are bonded to each other to form an optionally substituted ring,is a glucokinase activator (patent document 2).    (3) It has been reported that a compound represented by the formula:
wherein    R1 is an optionally substituted aryl group or an optionally substituted heteroaryl group;    R11 is an optionally substituted aryl group, a 5- to 7-membered aliphatic heterocyclic group, or an optionally substituted 5- or 6-membered heteroaryl group;    R2 is formyl, OH, a C1-6 alkyl group, —CH3-aFa, —OCH3-aFa (a is 1-3), amino, cyano, a halogen atom or —(CH2)1-4—OH;    R3 is a C1-6 alkyl group, —(CH2)1-6—OH, —C(O)—OC1-6 alkyl, —(CH2)1-6—OC1-6 alkyl, —(CH2)1-6—NH2, cyano, —C(O)—C1-6 alkyl, a halogen atom, a C2-6 alkenyl group, —O—C1-6 alkyl, —COOH or OH;    R4 is a hydrogen atom or a C1-6 alkyl group;    Y is a carbon atom or a nitrogen atom;    Z1 is —O—, —S—, —S(O)— or S(O)2—;    Z2 is —O—, —S—, —S(O)—, S(O)2— or —CH2— (optionally substituted by a halogen atom, a C1-6 alkyl group etc.), or a single bond;    at least two of Y1, Y2, Y3 and Y4 are each independently a carbon atom and the rest is a carbon atom or a nitrogen atom;    ring A is a heteroaryl group;    X is a carbon atom or a nitrogen atom;    m is 0-2; and    q is 0-2,is a glucokinase activator and useful for the treatment of diabetes, obesity and the like (patent document 3).    (4) It has been reported that a compound represented by the formula:
wherein    R1 is a hydrogen atom or halogen;    R2 is
wherein    A is CH or N;    R4 and R5 are each an optionally substituted C1-6 alkyl or optionally substituted C3-10 cycloalkyl, and R4 and R5 form an optionally substituted ring (the ring is not morpholine);    R6, R7, R21 and R22 are each a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group or an acyl group, and R6 and R7 form an optionally substituted ring;    W is an oxygen atom or NR8 (R8 is a hydrogen atom, an optionally substituted C1-6 alkyl group or an optionally substituted C3-10 cycloalkyl group);    R3 is an optionally substituted heterocyclic group or an optionally substituted C6-14 aryl group; and    R9, R10 and R11 are each a hydrogen atom, halogen, an optionally substituted C1-6 alkyl group or an optionally substituted C1-6 alkoxy group;    provided that when R21 is a hydrogen atom or C1-6 alkoxycarbonyl and R22 is a hydrogen atom, then R6 and R7 are not simultaneously hydrogen atoms or methyl groups,is a glucokinase activator and useful for the treatment of diabetes, obesity and the like (patent document 4).    (5) It has been reported in patent document 5 that an indole derivative represented by the formula:
is useful for an antirheumatism treatment, an anticancer treatment and an antivirus infection treatment (patent document 5).    (6) It has been reported in patent document 6 that an indole derivative represented by the formula:
is a PDGF antagonist (patent document 6).    (7) In non-patent document 1, an indole derivative represented by the formula
(non-patent document 1) is reported.    (8) It has been reported that a compound represented by
wherein    ring A is a 6-membered ring which may be further substituted;    ring B is an optionally substituted 5- or 7-membered nitrogen-containing heterocycle;    W1 and W2 are each independently O, S, SO, SO2 or NR4 (R4 is a hydrogen atom or a C1-6 alkyl group);    R1 is a substituted methyl group, an optionally substituted C2-6 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted C6-14 aryl group or an optionally substituted heterocyclic group;    R2 is an optionally substituted C1-6 alkyl group or an optionally substituted C3-10 cycloalkyl group;    R3 is a hydrogen atom or a halogen atom, (excluding N-methyl-4-[(1-methyl-1H-tetrazol-5-yl)thio]-2-(1,3-thiazol-2-yl)-1H-indole-7-amine) is a glucokinase activator, and useful for the treatment of diabetes, obesity and the like (patent document 7).
However, none of the documents disclose a compound represented by the following formula (I).    patent document 1: WO2005/049019    patent document 2: WO2006/112549    patent document 3: WO2007/037534    patent document 4: WO2008/050821    patent document 5: WO2006/089397    patent document 6: JP-A-2007-099630    patent document 7: WO2009/125873    non-patent document 1: Synthetic Communications, 38(3), 361-370, 2008